Cefmenoxime hydrochloride has a chemical name of (6R,7R)-7-[(Z)-2-(2-amino-thiazol-4-yl)-2-methoxyiminoacetylamino]-3-[[(1-methyl-1H-tetrazol-5-yl)-sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride (2:1) with many synonyms such as Bestcall, Azole cephalosporin cefotaxime, Cefmenoxime, Azole hydrochloride cephalosporin cefotaxime, and Cefotaxime azole. It has a chemical formula of (C16H17N9O5S3)2.HCl with a molecular weight of 1059.58. The structural formula is
Cephalosporins, a β-lactam antibiotic, are a fastest growing antibiotic in the world in recent years with many new varieties. They are an efficient antibiotic with low toxicities. Cefmenoxime hydrochloride is the third-generation semi-synthetic broad-spectrum cephalosporin antibiotic, which was first developed by Takeda Pharmaceutical Co., Ltd. and has been marketed in Japan since 1983. It has entered the latest version of the Pharmacopoeia of Europe and many other countries, and has been marketed in China since 2000.
The key characteristic of the chemical structure of Cefmenoxime hydrochloride is that the acylation of C7-amino side chain and the introduction of methoxy at the 7a position to impart Cefmenoxime hydrochloride a broad-spectrum antibacterial activity. It inhibits cell wall biosynthesis to achieve a bactericidal effect, and has the stability against β-lactamase, and can be used to treat a variety of bacterial infections caused by inflammation with a significant effect (see: Liu Shu Jing, Chen Yaozu. The Research Progress in C3-position Functionalization of Cephalosporins and Synthetic Intermediates thereof [J]. World Notes on Antibiotics. 1999, 20 (6): pages 241ff; and Nishimura T, Tabuki K, Hiromatsu K et al, Laboratory and clinical studies of cefmenoxime in the pediatric field [J]. Jpn J Antibiot, 1982, 35 (11): 2535-2544).
At present, there are two synthetic routes for producing Cefmenoxime hydrochloride in China: (i) the modification of the side chain at C3 position of 7-ACA and then the amino side chain at C7 position: and (ii) the modification of the amino side chain at C7 position of 7-ACA and then the side chain at C3 position. In these two synthetic routes, Cefmenoxime is prepared and isolated, and then vacuum dried to obtain dry Cefmenoxime acid which is re-dissolved, and then forms salt, and finally yields the finished Cefmenoxime hydrochloride.
Zheng Yimei reported a one-pot Cefmenoxime hydrochloride synthesis technology in the Chinese Journal of Antibiotics 33 (5) May (2008). It starts with 3-(1-methyl-1H-tetrazol-5-yl)methyl-7-aminocephalosporanic acid hydrochloride (i.e., 7-ATCA.HCl) available from many manufacturers in China which, as the intermediate, undergoes the condensation reaction with 2-(2-amino-thiazol-4-yl)-2-methoxy imine-acetyl-benzothiazolyl thioester (i.e., AE active ester) to yield Cefmenoxime acid and then forms salt without separation in the reaction solution in a one-pot manner, resulting in Cefmenoxime hydrochloride. Although the process is simplified, the reaction intermediates and reagents tend to be incorporated into the final product.
Pharmaceutical Co. Ltd. Hainan Tianhuang disclosed a method for producing Cefmenoxime hydrochloride in CN101555251A, wherein 7-ATCA, as the starting materials, undergoes a condensation reaction with active ester (AE) to form sodium 7-[α-(2-amino-thiazol-4-yl)-Z-2-methoxyimino acetamido]-3-(1-methyl-1H-5-tetrazolyl-thiomethyl)-3-cephem-4-carboxylate (i.e., sodium Cefmenoxime), and then reacts with 10% hydrochloric acid to yield Cefmenoxime hydrochloride. However, the yield and purity of Cefmenoxime hydrochloride prepared by this method is not high, and moreover triethylamine and ethylene dichloride are used during the preparation the residue of which has a negative impact on the human body.
Chinese patent CN101348494 has disclosed a purification method for refining Cefmenoxime hydrochloride, wherein a macroporous resin is used for adsorption and separation prior to purification by gel column. However, since the adsorption and elution is incomplete, the yield and purity is not ideal, and it is difficult to separate the inherent impurities in Active Pharmaceutical Ingredients.
At present, most Chinese manufacturers of Cefmenoxime hydrochloride formulations rely on imports of Active Pharmaceutical Ingredients for packing drugs, although a few Chinese manufacturers produce the product by themselves, but the yield and purity of the product is not very high. Therefore, improving the purity of Cefmenoxime hydrochloride is an urgent problem with significant social and economic benefits.